Several different forms of non-apoptotic death have, based on specific morphological or molecular criteria. These include death associated with accumulation of autophagosomes, as well as several types of caspase-independent cell death that can represent specialized forms of necrosis; e.g., oncosis, necroptosis and paraptosis. A unique type of non-apoptotic cell death can be induced in glioblastoma and gastric carcinoma cells by constitutive stimulation of Ras signaling pathways. This unique form of cell death is distinct from other kinds of non-apoptotic death noted above. It involves stimulation of macropinocytosis (cell drinking), combined with defects in clathrin-independent endocytic vesicle trafficking, ultimately resulting in accumulation of large vacuoles that disrupt cellular membrane integrity. The unique form of cell death is termed “methuosis,” from the Greek methuo, to drink to intoxication. Mechanistically, the effects of Ras overexpression are related to activation of Rac1 and inactivation of Arf6, two GTPases implicated in macropinocytosis and endosome recycling, respectively.
Cancer cells typically harbor mutations in tumor suppressor genes that control programmed cell death, rendering them relatively insensitive to apoptosis. Moreover, many tumors that initially respond to treatment with chemotherapeutic drugs eventually develop multi-drug resistance due to increases in drug efflux mechanisms or DNA repair capacity. These challenges have stimulated interest in identifying alternative cell death pathways that can be used to kill tumor cells that have ceased to respond to drugs that depend on induction of apoptotic mechanisms.